2-methyl-thieno-benzodiazepine

ABSTRACT

2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine, or an acid salt thereof, has pharmaceutical properties, and is of particular use in the treatment of disorders of the central nervous system. The compound has the following structure: ##STR1##

This application is a continuation of application Ser. No. 07/690,143,filed on Apr. 23, 1991 now abandoned.

This invention relates to novel organic compounds and the use thereof aspharmaceuticals.

Currently there are many drugs available for the treatment of disordersof the central nervous system. Amongst these drugs is a category knownas antipsychotics for treating serious mental conditions such asschizophrenia and schizophreniform illnesses. The drugs available forsuch conditions are often associated with undesirable side effects, andthere is a need for better products that control or eliminate thesymptoms in a safer and more effective way. Furthermore, many patientsdo not respond or only partially respond to present drug treatment, andestimates of such partial- or non-responders vary between 40% and 80% ofthose treated.

Ever since antipsychotics were introduced it has been observed thatpatients are liable to suffer from drug-induced extra pyramidal symptomswhich include drug-induced Parkinsonism, acute dystonic reactions,akathisia, tardive dyskinesia and tardive dystonia. The Simpson AngusScale, Barnes Akathisia Rating Scale and Abnormal Involuntary MovementScale (AIMS) are well known scales for assessing extra pyramidalsymptoms. The great majority of drugs available for treatment ofschizophrenia are prone to produce these extra pyramidal side effectswhen used at dosages that yield a beneficial effect on the symptoms ofthe disease. The severity of adverse events and/or lack of efficacy in aconsiderable number of patients frequently results in poor compliance ortermination of treatment.

Many of the drugs are associated with a sedative effect and may alsohave an undesirable influence on the affective symptoms of the disease,causing depression. In some instances long term use of the drug leads toirreversible conditions, such as the tardive dyskinesia and tardivedystonia referred to above.

A widely-used antipsychotic, haloperidol, is one such drug, which hasbeen reported as causing a high incidence of extra pyramidal symptomsand may also cause tardive dyskinesia. More recently, clozapine, one ofa large group of tricyclic antipsychotics, has been introduced with theclaim that it is free from extra pyramidal effects. However, thecompound was found to cause agranulocytosis in some patients, acondition resulting in a lowered white blood cell count which can belife-threatening, and it may now only be employed under very strictmedical observation and supervision.

A further group of antipsychotic compounds is that described in BritishPatent 1 533 235. These include thienobenzodiazepines having thefollowing structural nucleus. ##STR2## The lead compound from thisgroup, flumezapine,(7-fluoro-2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]-benzodiazepine),was developed to the stage of being clinically administered topsychiatric patients suffering from schizophrenia. A total of 17patients received treatment with flumezapine before the clinical trialwas terminated after consultation with the U.S. Food and DrugAdministration, because of an unacceptably high incidence of raisedenzyme levels in the treated patients. The enzyme, creatininephosphokinase (CPK), and the liver enzymes, serum glutamate oxalacetictransaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT),estimated from blood samples taken from patients, were in substantialexcess of normal values, indicating the possibility of toxicity. Inrespect of its tendency to raise liver enzyme levels, flumezapine issimilar to chlorpromazine, an antipsychotic which has long been in usebut whose safety has been called into question.

In clinical trials with flumezapine two of the patients showed theemergence of extra pyramidal side effects as measured on the AIMS scalereferred to above.

We have now discovered a compound which possesses surprising andunexpected properties by comparison with flumezapine and other relatedcompounds.

The compound of the invention is of the formula ##STR3## or an acidaddition salt thereof. The free base of formula (I) is2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b]-[1,5]benzodiazepine.

The compound of the invention has given surprising and excellentresults, described in greater detail below, in experimental screens fortesting activity on the central nervous system and in clinical trials,which results indicate its usefulness for the relatively safe andeffective treatment of a wide range of disorders of the central nervoussystem.

The results of pharmacological tests show that the compound of theinvention is an antagonist of dopamine at D-1 and D-2 receptors, and inaddition has antimuscarinic anti-cholinergic properties and antagonistactivity at 5HT-2 receptor sites. It also has antagonist activity atnoradrenergic α-receptors. These properties indicate that the compoundis a potential neuroleptic with relaxant, anxiolytic or anti-emeticproperties, and is useful in treating psychotic conditions such asschizophrenia, schizophreniform diseases and acute mania. At lower dosesthe compound is indicated for use in the treatment of mild anxietystates.

As mentioned above, the compound of the invention has shown a high levelof activity in the clinical evaluation of psychiatric patients sufferingfrom schizophrenia, and it exhibits this high activity at surprisinglylow dosage levels. The dosage levels have been found to be lower thanwould be expected from observations of the compound made in initialtests on animal models. Its response profile in patients follows that ofknown antipsychotic agents when they have been used successfully, therebeing a clear similarity between the performance of the compound andthat of known antipsychotic agents in its ratings on the majorassessment scales such as Brief Psychiatric Rating Scale (BPRS)(Schizophrenia Sub-scale), and Clinical Global Impression (CGI).

In the first completed open (as opposed to blind) study of the compoundof the invention in schizophrenic patients, six out of eight patientswho completed at least 2 weeks of treatment showed between 66% and 87%improvement at 4 weeks, as assessed on BPRS scale, at daily dosagesbetween 5 and 30 mg. Preliminary results from a further three ongoingclinical trials now appear to confirm this high level of efficacy and atdoses lower than or at the low end of the dosage level used in the firststudy, for example, at 2.5 and 5 mg per day.

Moreover, there is a low incidence of only mild and transient elevationof liver enzymes in patients treated with therapeutic doses, and plasmalevels of creatinine phosphokinase (CPK) are lower than withflumezapine, indicating a lower adverse effect on muscular tissue.Furthermore, the compound of the invention causes lower elevation ofprolactin levels than other currently used neuroleptic drugs and thissuggests fewer disturbances of the menstrual cycle, and lessgynecomastia and galactorrhea. No alteration of white blood cell counthas been observed in clinical studies.

In dog toxicity studies with a closely analogous compound,2-ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b]-[1,5]benzodiazepine,at a dosage of 8 mg/kg, it was observed that four out of eight dogsshowed a significant rise in cholesterol levels, whereas the compound ofthe invention did not show any rise in cholesterol levels.

Overall, therefore, in clinical situations, the compound of theinvention shows marked superiority, and a better side effects profilethan prior known antipsychotic agents, and has a highly advantageousactivity level.

The compound of the invention can be used both in its free base and acidaddition salt forms. The acid addition salts are preferably thepharmaceutically acceptable, non-toxic addition salts with suitableacids, such as those of inorganic acids, for example hydrochloric,hydrobromic, nitric, sulphuric or phosphoric acids, or of organic acids,such as organic carboxylic acids, for example glycollic, maleic,hydroxymaleic, fumaric, malic, tartaric, citric or lactic acid, ororganic sulphonic acids for example methane sulphonic, ethane sulphonic,2-hydroxyethane sulphonic, toluene-p-sulphonic ornaphthalene-2-sulphonic acid. In addition to pharmaceutically acceptableacid addition salts, other acid addition salts are included in theinvention, for example, those with picric or oxalic acid, since theyhave potential to serve as intermediates in purification or in thepreparation of other, for example, pharmaceutically acceptable, acidaddition salts, or are useful for identification, characterisation orpurification of the free base.

According to a further aspect of the invention there is provided aprocess for producing a compound of formula (I) or an acid addition saltthereof, which comprises

(a) reacting N-methylpiperazine with a compound of the formula ##STR4##in which Q is a radical capable of being split off, or

(b) ring-closing a compound of the formula ##STR5##

Appropriate reaction conditions and suitable values of Q can readily bechosen for these processes.

In reaction (a) the radical Q can, for example, be an amino group or amono- or dialkyl-substituted amino group (each alkyl substituentsuitably containing 1 to 4 carbon atoms), hydroxyl, thiol, or an alkoxy,alkylthio or alkylsulphonyl group suitably containing 1 to 4 carbonatoms, for example a methoxy or methylthio group, or a halogen atom,especially a chlorine atom. Preferably, Q is amino (--NH₂), hydroxyl orthiol, and amino is most preferred. The reaction is preferably carriedout at a temperature of from 50° C. to 200° C.

When Q is amino, the intermediate of formula (II) may also exist in theimino form: ##STR6## and when Q is hydroxyl or thiol, the intermediatesof formula (II) may exist in their amide and thioamide forms: ##STR7##

The amidine of formula (II) (Q is --NH₂), can be in salt form, forexample a salt of a mineral acid such as the hydrochloride, and can bereacted with N-methylpiperazine in an organic solvent such as anisole,toluene, dimethylformamide or dimethyl-sulphoxide, preferably at atemperature range of 100° to 150° C.

The amidine is prepared by condensing a thiophene compound of formula##STR8## with an ortho-halonitrobenzene, in the presence of a base, forexample sodium hydride, in a solvent such as tetrahydrofuran or n-butyllithium in tetrahydrofuran, or potassium carbonate or lithium hydroxidein dimethylsulphoxide or with a tetraalkylammonium salt in a two-phasesystem, to form a nitronitrile of formula: ##STR9## which can besimultaneously reduced and ring-closed to the amidine of formula (II)employing, for example, stannous chloride and hydrogen chloride inaqueous ethanol or, alternatively by reduction with hydrogen andpalladium/carbon or ammonium polysulphide followed by acid-catalysedring closure.

When Q is hydroxyl, reaction (a) is preferably carried out in thepresence of titanium tetrachloride which has the ability to react withthe N-methylpiperazine to form a metal amine complex. Other metalchlorides such as those of zirconium, hafnium or vanadium may also beemployed. The reaction can be carried out in the presence of an acidbinding agent such as a tertiary amine, for example, triethylamine.

Alternatively, the reaction can be carried out using excess ofN-methylpiperazine to act as an acid-binding agent. A suitable organicsolvent such as toluene or chlorobenzene can be used as a reactionmedium, although the use of anisole is particularly desirable, at leastas a co-solvent, in view of its ability to form a soluble complex withTiCl₄.

If desired, elevated temperatures, for example up to 200° C., can beused to hasten the reaction and a preferred temperature range forcarrying out the reaction is from 80° C. to 120° C.

The intermediate amide of formula (II) (Q is --OH) can be prepared fromthe corresponding amidine (Q is --NH₂) by alkaline hydrolysis, or can bederived from compounds of formula ##STR10## in which R is an estergroup, preferably C₁₋₄ alkyl, by ring closure employing, for example,sodium methylsulphinyl methanide in a suitable solvent such asdimethylsulphoxide. Alternatively, the amide can be prepared by ringclosure of an amino-acid, employing for exampledicyclo-hexylcarbodiimide (DCC) in a suitable solvent such astetrahydrofuran. The amino-acid can be obtained for example from theabove esters by basic hydrolysis using for example sodium hydroxide inethanol.

Thioamides of formula (II) (Q is --SH), iminothioethers, iminoethers oriminohalides, or other derivatives containing active Q radicals asspecified above, tend to be more reactive towards N-methylpiperazine andcan usually be reacted without the necessity for the presence of TiCl₄,but otherwise employing the same conditions of temperature and solvent.

The thioamide of formula (II) (Q is --SH) can be prepared by treating asolution of the corresponding amide in an anhydrous basic solvent, suchas pyridine, with phosphorous pentasulphide. Similarly, the amide can beconverted to the iminothioether, iminoether or iminohalide, or otherderivatives containing active Q radicals, by treatment with conventionalreagents such as for example in the case of the iminochloride,phosphorous pentachloride.

The intermediate compounds of formula (II) in which Q is a radicalcapable of being split off, particularly those in which Q is --NH₂, --OHor --SH and when Q is --NH₂ salts thereof, are novel compounds, and forma further aspect of the present invention.

With regard to reaction (b) above, the compound of formula (III) may bering-closed by employing, for example, titanium tetrachloride ascatalyst and anisole as solvent, and the reaction is preferably carriedout at a temperature of 100° C. to 250° C., for example from 150° C. to200° C.

The intermediate compound of formula (III) is preferably prepared insitu without isolation by reacting a compound of formula ##STR11## inwhich R is an ester group, preferably C₁₋₄ alkyl, withN-methylpiperazine, by heating to a temperature of between 30° C. and120° C., for example about 100° C., in a suitable solvent such as forexample anisole, and employing TiCl₄ as catalyst.

The compound of formula (IV) can be prepared from the correspondingnitro compound of formula ##STR12##

Such compounds of formula (V) in which R is an ester group, such as forexample C₁₋₄ alkyl, are novel and form a further aspect of theinvention.

If convenient this nitro compound can be converted to the amine offormula (IV) without isolation, before reaction with N-methylpiperazine.Intermediate compounds of formula (V) can be made by condensation of athiophene of formula ##STR13## with an ortho-halonitrobenzene,preferably ortho fluoro- or chloro- nitrobenzene, in the presence of abase, for example, (a) sodium hydride in a solvent such as for exampletetrahydrofuran and at a temperature of from -20° C. to 30° C., or (b)anhydrous potassium carbonate or lithium hydroxide in a solvent such asdimethylsulphoxide at a temperature of from 90° C. to 120° C. Thecompound of formula (V) is converted to that of formula (IV) byreduction, for example catalytically, employing hydrogen andpalladium/carbon, or chemically, employing stannous chloride andhydrogen chloride in aqueous ethanol, or ammonium polysulphide, or zincin aqueous ammonium chloride.

It will be appreciated that the compound of formula (I) may be isolatedper se or may be converted to an acid addition salt using conventionalmethods.

As mentioned above, the compound of the invention has useful centralnervous system activity. This activity has been demonstrated in modelsusing well-established procedures. For example, the compound has beenassessed in a number of standard behavioural tests predictive ofantipsychotic activity. It antagonised apomorphine-induced climbingbehaviour and hypothermia in mice (Moore, N. A. et al.Psychopharmacology 94 (2), 263-266 (1988), and 96, 539 (1988)) at dosesof less than 10 mg/kg. The compound also inhibited a conditionedavoidance response in rats (ED₅₀ 4.7 mg/kg), but unlike standardcompounds, it induced catalepsy only at much higher doses (ED₅₀ 39.4mg/kg). This separation between the doses required to block aconditioned avoidance response and to induce catalepsy indicates thatthe compound is less likely to induce extrapyramidal side effects in theclinic.

The compound of the invention was also active at doses of less than 10mg/kg in a test based on the apomorphine-induced climbing test referredto above, which measured the ability of the compound to prevent thedisruption of climbing response produced by 24 hour pre-treatment withN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), a dopaminereceptor inactivating agent (Meller et al. Central D1 dopaminereceptors, Plenum Press, 1988). This test shows that the compoundpossesses activity at both the D-1 and D-2 receptors.

In addition, the compound of the invention has been found to have afavourable profile of activity in a number of in vitro binding assays,designed to measure the degree of binding to neural receptors.

In keeping with the observations made in the behavioural tests, thecompound is active at both the dopamine D-1 and D-2 receptors asindicated by an IC₅₀ of less than 1 μM in the ³ H-SCH23390 (Billard, W.et al. Life Sciences 35 1885 (1984)) and the ³ H-spiperone (Seeman, P.et al. Nature 261 717 (1976)) binding assays respectively.

The compound has an IC₅₀ of less than 1 μM in the ³ H-QNB binding assaydescribed by Yamamura, HI and Snyder, SH in Proc. Nat. Acad. Sci. USA 711725 (1974) indicating that it has antimuscarinic-anticholinergicactivity. In addition, the compound shows its greatest activity at the5-HT-2 receptor in that it displaces H-spiperone from binding sites inthe rat frontal cortex (Peroutka, SJ and Snyder, SH Mol. Pharmacol. 16687 (1979)) at low nanomolar concentrations. The compound is also activeat the 5-HT-IC receptor.

This profile of activity in in vitro receptor binding assays, like thatobserved in the behavioural tests, would indicate that the compound iseffective in the treatment of psychotic conditions but is less likely toinduce extra pyramidal side-effects.

The compound of the invention is effective over a wide dosage range, theactual dose administered being dependent on the condition being treated.For example, in the treatment of adult humans, dosages of from 0.05 to30 mg, preferably from 0.1 to 20 mg, per day may be used. A once a daydosage is normally sufficient, although divided doses may beadministered. For treatment of psychotic disorders a dose range of from2 to 15 mg, preferably 2.5 to 10 mg per day is suitable, whereas formild anxiety states a lower dosage range, such as from 0.1 to 5 mg,preferably 0.5 to 1 mg, may be more appropriate. In choosing a suitableregimen for patients suffering from psychotic illness it may frequentlybe necessary to begin with a dosage of from 2 to 15 mg per day and whenthe illness is under control to reduce to a dosage as low as from 0.5 to1 mg per day. In studies using radiolabelled compound of the invention,residues have been detected in the saliva and thus the compound canpotentially be monitored in patients to assess compliance.

The compound of the invention will normally be administered orally or byinjection and, for this purpose, it is usually employed in the form of apharmaceutical composition.

Accordingly the invention includes a pharmaceutical compositioncomprising as active ingredient a compound of formula (I) or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable carrier. In making the compositions of theinvention conventional techniques for the preparation of pharmaceuticalcompositions may be used. For example, the active ingredient willusually be mixed with a carrier, or diluted by a carrier, or enclosedwithin a carrier which may be in the form of a capsule, sachet, paper orother container. When the carrier serves as a diluent, it may be solid,semi-solid or liquid material which acts as a vehicle, excipient ormedium for the active ingredient. The active ingredient can be adsorbedon a granular solid container for example in a sachet. Some examples ofsuitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol,starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin,syrup, methyl cellulose, methyl- and propyl-hydroxy-benzoate, talc,magnesium stearate or mineral oil. The compositions of the inventionmay, if desired, be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient.

Depending on the method of administration, the compositions may beformulated as tablets, capsules, injection solutions for parenteral use,suspensions or elixirs for oral use or suppositories. Preferably thecompositions are formulated in a dosage unit form, each dosagecontaining from 0.1 to 20 mg, more usually 0.5 to 10 mg, of the activeingredient.

A preferred formulation of the invention is a capsule or tabletcomprising 0.1 to 20 mg or 0.5 to 10 mg of active ingredient togetherwith a pharmaceutically acceptable carrier therefor. A further preferredformulation is an injection which in unit dosage form comprises 0.1 to20 mg or 0.5 to 10 mg of active ingredient together with apharmaceutically acceptable diluent therefor. A type of injectionformulation that is especially desirable is a sustained releaseformulation for intra-muscular injection.

The invention is illustrated by the following Examples.

EXAMPLE 1

1. 2-Amino-5-methylthiophene-3-carbonitrile

A mixture of sulphur (217.8 g, 6.79 mol), propionaldehyde (472.5 g, 587mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 literflange-necked flask fitted with air stirrer, air condenser, long reachthermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) wasadded dropwise over 30 minutes to the cooled stirred reaction mixturewhilst maintaining the pot temperature between 5°-10° C. with anice-bath. After addition was complete the pot was allowed to warm up to18° C. over 50 minutes, keeping the mixture well stirred. Then asolution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL)was added dropwise over 70 minutes keeping the pot temperature around20° C. throughout the addition. After addition was complete the mixturewas stirred at 15°-20° C. for a further 45 minutes then sampled for TLC.The mixture was then poured onto ice (4 liters)/water (8 liters) withstirring and this caused the required product to precipitate. After 10minutes the stirrer was switched off and the solid allowed to settle.The aqueous liquor was decanted away and the solid isolated byfiltration. The isolated solid was well washed with water (de-ionised, 4liters), then dried over night in vacuo at 70°-75° C. to give the titlecompound (585 g), m.p. 100° C.

2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile

To a stirred slurry of sodium hydride (14.4 g, 50% dispersion in oil,0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added,dropwise, a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and2-amino-5-methylthiophene3-carbonitrile (27.6 g, 0.2 mol) in drytetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24hours, poured onto cracked ice and extracted into dichloromethane (3×500mL). The combined extracts were washed with 2N hydrochloric acid (2×200mL), water (2×200 mL), dried over magnesium sulphate and the solventremoved under reduced pressure. The residue was crystallised fromethanol to give the title compound, (35.2 g), m.p. 99°-102° C.

3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride

To a stirred slurry of2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (3 g, 0.011 mol) inethanol (35 mL) at 50° C. was added, over 10 minutes, a solution ofanhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26mL, 5M). The mixture was stirred under reflux for 1 hour, concentratedunder reduced pressure and allowed to crystallise over night at 5° C.The salt was filtered, washed with a small amount of water, dried (4.3g) m.p. >250° C., and used without further purification in the nextstage.

4.2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]-benzodiazepine

Crude 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine,hydrochloride (4.3 g) was refluxed in a mixture of N-methylpiperazine(15 mL), dimethylsulphoxide (20 mL) and toluene (20 mL) under a nitrogenatmosphere for 20 hours. The mixture was cooled to ca. 50° C., water (20mL) added, and the product allowed to crystallise at 5° C. over night.The product was filtered and crystallised from acetonitrile (30 mL) togive the title compound (1.65 g) m.p. 195° C.

The structure of the compound was confirmed spectroscopically: ##STR14##

¹ H NMR (CDCl₃): δ2.30 (3H, s, 4'-CH₃), 2.28 (3H, s, 2-CH₃), 2.45 (4H,m, 3'-CH₂) 3.49 (4H, m, 2'-CH₂), 5.00 (H, broad s, 10-NH), 6.23 (H,broad s, 3-CH), 6-35-7-10 (4H, m, 6,7,8,9-H).

³ C NMR (CDCl₃): δ128.5 (s, C-2), 127.8 (d, C-3), 119.1 (s, C-3a), 157.4(s, C-4) 140.8 (s, C-5a), 123.4, 122.6, 124.1 (d, C-6,7,8), 118.8 (d,C-9), 142.5 (s, C-9a), 151.8 (s, C-10a), 46.5 (t, 2'-C), 54.8 (t, 3'-C)45.9 (q, -4'-C), 15.2 (q, 2-Me).

Mass spectra shows an M⁺ of 312 and major fragment ions of m/z 255, 242,229 and 213.

EXAMPLE 2

1. Methyl 2-amino-5-methylthiophene-3-carboxylate

To a stirred mixture of methyl cyanoacetate (3.9 g, 0.04 mol), sulphur(1.26 g, 0.04 mol) and triethylamine (3.2 mL, 002 mol) in drymethylformamide (12 mL) under a nitrogen atmosphere at 45° C. was added,dropwise, a solution of freshly distilled propionaldehyde (2.5 g, 0.043mol) in dry dimethylformamide (2 mL), keeping the temperature at 45°-47°C. The mixture was stirred at 45° C. for 1.5 hours, then partitionedbetween water and ethyl acetate. The organic extract was washed withwater, dried and evaporated. The title compound was purified bychromatography on neutral alumina, eluting with chloroform-hexane (4.8g).

2. Methyl 2-(2-nitroanilino)-5-methylthiophene-3-carboxylate

To a stirred suspension of sodium hydride (2 g) in dry tetrahydrofuran(25 mL) under a nitrogen atmosphere was added a solution of methyl2-amino-5-methylthiophene-3-carboxylate (4.8 g, 0.028 mol) and2-fluoronitrobenzene (4.0 g, 0.025 mol) in dry tetrahydrofuran (30 mL).The mixture was stirred at 25° C. for 20 hours, poured onto ice andpartitioned between 2N hydrochloric acid and ethyl acetate. The organicextracts were dried over magnesium sulphate, the solvent was evaporatedunder reduced pressure and the title compound purified by chromatographyon silica gel, eluted with toluene, and crystallised from ethanol (4.1g).

3.2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine

Methyl 2-(2-nitroanilino)-5-methylthiophene-3-carboxylate (3.7 g, 0.0013mol) was hydrogenated in a Parr apparatus at 60 psi in ethanol-ethylacetate (2:1, 150 mL) with palladium on charcoal catalyst (10%, 200 mg).After removal of catalyst and solvent the crude diamino-ester wasdissolved in a mixture of N-methylpiperazine (21 mL) and anisole (55mL). To this solution, under a nitrogen atmosphere was added, withstirring, a solution of titanium tetrachloride (3.45 mL) in anisole (15mL). The mixture was stirred at 100° C. for 1 hour, then under refluxfor 48 hours to effect ring closure of1-{[2-(2-aminoanilino)-5-methylthiophen-3-yl]carbonyl}-4-methylpiperazine.

After allowing to cool to 80° C. a mixture of 30% ammonia solution (10mL) and isopropanol (10 mL) was cautiously added, followed by ethylacetate (25 mL). The inorganic precipitate was removed by filtration andthe filtrate washed with water (3×25 mL), dried with magnesium sulphateand the solvent removed under reduced pressure. The product was purifiedby chromatography on Florisil, eluted with ethyl acetate and finallycrystallised from acetonitrile (40 mL) to give the title compound (2.32g), identical with that described above.

EXAMPLE 3

A pulvule formulation is prepared by blending the active with siliconestarch, and filling it into hard gelatin capsules.

    ______________________________________                                                        Per 300 mg capsule                                            ______________________________________                                        Compound of the invention                                                                       5.0 mg                                                      Silicone          2.9 mg                                                      Starch flowable   292.1 mg                                                    ______________________________________                                    

EXAMPLE 4

A tablet formulation is made by granulating the active with appropriatediluent, lubricant, disintegrant and binder and compressing

    ______________________________________                                        Compound of the invention                                                                             5.0 mg                                                Magnesium stearate      0.9 mg                                                Microcrystalline cellulose                                                                            75.0 mg                                               Povidone                15.0 mg                                               Starch, directly compressible                                                                         204.1 mg                                              ______________________________________                                    

EXAMPLE 5

An aqueous injection of active is prepared as a freeze-dried plug, forreconstitution in a suitable, sterile diluent before use (to a totalvolume of 10 ml).

    ______________________________________                                        Compound of the invention                                                                            20.0 mg                                                Mannitol               20.0 mg                                                N Hydrochloric acid and/or N sodium                                           hydroxide to adjust pH to 5-5.5.                                              ______________________________________                                    

EXAMPLE 6

A controlled release injection for intramuscular injection is formedfrom a sterile suspension of micronised active in an oleaginous vehicle.

    ______________________________________                                        Compound of the invention                                                                             65.0   mg                                             Aluminium stearate      0.04   mg                                             Sesame oil              2      ml                                             ______________________________________                                    

EXAMPLE 7

A formulation is prepared by blending the active with silicone starchand starch, and filling it into hard gelatine capsules.

    ______________________________________                                                           Per 290 mg capsule                                         ______________________________________                                        Compound of the invention                                                                           2.5 mg                                                  Starch flowable with 0.96%                                                                         217.5 mg                                                 silicone 220                                                                  Starch flowable       70.0 mg                                                 ______________________________________                                    

We claim: 1.2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or an acid addition salt thereof.
 2. A pharmaceutical compositioncomprising a compound according to claim 1 or a pharmaceuticallyacceptable acid addition salt thereof together with a pharmaceuticallyacceptable diluent or carrier therefor.
 3. A pharmaceutical compositionin capsule or tablet form comprising from 2.5 to 5 mg of the compound ofclaim 1 together with a pharmaceutically acceptable diluent or carriertherefor.
 4. A method of treating an animal, including a human,suffering from or susceptible to psychosis, acute mania or mild anxietystates, which comprises administering an effective amount of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition salt thereof.
 5. A methodof claim 4 for treating an animal, including a human, suffering from orsusceptible to psychosis.
 6. A method of claim 5 wherein the effectiveamount is from 0.1 to 20 mg per day of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition salt thereof.
 7. A methodof claim 5 for treating an animal, including a human, suffering from orsusceptible to schizophrenia.
 8. A method of claim 7 wherein theeffective amount is from 0.1 to 20 mg per day of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition solution salt thereof. 9.A method of claim 5 for treating an animal, including a human, sufferingfrom or susceptible to schizophreniform diseases.
 10. A method of claim9 wherein the effective amount is from 0.1 to 20 mg per day of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition salt thereof.
 11. Amethod of claim 4 for treating an animal, including a human, sufferingfrom or susceptible to acute mania.
 12. A method of claim 11 wherein theeffective amount is from 0.1 to 20 mg per day of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition salt thereof.
 13. Amethod of claim 4 for treating an animal, including a human, sufferingfrom or susceptible to mild anxiety states.
 14. A method of claim 13wherein the effective amount is from 0.1 to 20 mg per day of2-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[2,3-b][1,5]benzodiazepine,or a pharmaceutically acceptable acid addition salt thereof.
 15. Apharmaceutical composition in capsule or tablet form comprising from 0.1to 20 mg of the compound of claim 1 together with a pharmaceuticallyacceptable diluent or carrier therefor.